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Abstract:

Disclosed is a method of producing an optically active fluorinated
oxetane, which can be an important pharmaceutical or agricultural
intermediate, by reaction of a fluorinated α-keto ester with an
acyl alkenyl ether in the presence of a transition metal complex with an
optically active ligand. This method utilizes a catalytic asymmetric
synthesis process and does not require a stoichiometric amount of chiral
source. It is thus possible to dramatically reduce the amount of use of
the asymmetric catalyst especially when the reaction is performed at a
high concentration of substrate (with the use of a small amount of
reaction solvent) or in the absence of a reaction solvent (under neat
conditions). Further, the target optically active fluorinated oxetane can
be obtained with high yield and with very high optical purity. The
product contains almost no difficult-to-separate impurity and shows high
chemical purity.

Claims:

1. A method for producing an optically active fluorinated oxetane of the
general formula [3], comprising: reacting a fluorinated α-keto
ester of the general formula [1] with an acyl alkenyl ether of the
general formula [2] in the presence of a transition metal complex with an
optically active ligand, ##STR00044## where Rf represents a
perfluoroalkyl group; and R1 represents an alkyl group;
##STR00045## where R2, R3, R4 and R5 each
independently represent a hydrogen atom, an alkyl group, a substituted
alkyl group, an aromatic ring group or a substituted aromatic ring group;
and ##STR00046## where Rf, R1, R2, R3, R4 and
R5 are the same as above: * represents an asymmetric carbon atom
(when R4 and R5 are the same substituents, a carbon atom to
which R4 and R5 are bonded is not an asymmetric carbon atom);
and the wavy lines indicate that the configuration of acyloxy
(R2CO2) group relative to Rf and the configuration of R4
relative to Rf are each independently a syn configuration, an anti
configuration or a mixture thereof.

2. The method according to claim 1, wherein the optically active
fluorinated oxetane is of the general formula [6]; wherein the
fluorinated α-keto ester is of the general formula [4]; wherein the
acyl alkenyl ether is of the general formula [5]; and wherein the
transition metal complex with the optically active ligand is a divalent
cationic transition metal complex with an optically active ligand,
##STR00047## where R6 represents a methyl group or an ethyl group;
##STR00048## where R7 represents a hydrogen atom or an alkyl group;
and ##STR00049## where R6 and R7 are the same as above; *
represents an asymmetric carbon atom; and the wavy line indicates that
the configuration of acyloxy (R7CO2) group relative to CF3
group is a syn configuration, an anti configuration or a mixture thereof.

3. The method according to claim 2, wherein the divalent cationic
transition metal complex with the optically active ligand is a divalent
cationic palladium complex with an optically active ligand.

4. An optically active fluorinated oxetane of the general formula [3]
##STR00050## where Rf represents a perfluoroalkyl group; R1
represents an alkyl group; R2, R3, R4 and R5 each
independently represent a hydrogen atom, an alkyl group, a substituted
alkyl group, an aromatic ring group or a substituted aromatic ring group;
* represents an asymmetric carbon atom (when R4 and R5 are the
same substituents, a carbon atom to which R4 and R5 are bonded
is not an asymmetric carbon atom); and the wavy lines indicate that the
configuration of acyloxy (R2CO2) group relative to Rf and the
configuration of R4 relative to Rf are each independently a syn
configuration, an anti configuration or a mixture thereof.

5. The optically active fluorinated oxetane according to claim 4, wherein
the optically active fluorinated oxetane is of the general formula [6]
##STR00051## where R6 represents a methyl group or an ethyl group;
R7 represents a hydrogen atom or an alkyl group; * represents an
asymmetric carbon atom; and the wavy line indicates that the
configuration of acyloxy (R7CO2) group relative to CF3
group is a syn configuration, an anti configuration or a mixture thereof
relative to CF3 group.

Description:

TECHNICAL FIELD

[0001] The present invention relates to a method for producing an
optically active fluorinated oxetane, which can be an important
pharmaceutical or agricultural intermediate.

BACKGROUND ART

[0002] An optically active fluorinated oxetane of interest of the present
invention is a novel compound that can be an important pharmaceutical or
agricultural intermediate. There has however been reported no methods for
production of the optically active fluorinated oxetane. As shown in
Scheme 1, it is assumed that the optically active fluorinated oxetane is
a synthetic equivalent having on an asymmetric carbon atom thereof a
trifluoromethyl group and a hydroxyl group and can be derived into a
desired α,α-disubstituted optically active
β,β,β-trifluoroethanol by selective conversion of
formylmetyl and alkoxycarbonyl functional groups of different oxidation
levels.

##STR00001##

[0003] Suitable example of optically active fluorinated oxetane

[0004] Ra, Rb: desired substituent groups

[0005] Non-Patent Publications 1 to 3 report production methods of
compounds structurally different from, but relevant to, the optically
active fluorinated oxetane of interest of the present invention.

[0012] It is an object of the present invention to provide a method for
producing an optically active fluorinated oxetane, which can be an
important pharmaceutical or agricultural intermediate. Each of the
production methods of Non-Patent Publications 1 and 2 is intended for
production of the relevant compound as a racemic modification and thus
cannot be adopted for production of the target optically active compound
of the present invention. Further, the production method of Non-Patent
Publication 3 is intended for production of the optically active compound
but requires a plurality of process steps with the use of a
stoichiometric amount of chiral auxiliary.

[0013] There has thus been a strong demand to develop a practical
production method of a novel optically active fluorinated oxetane
compound that can be an important pharmaceutical or agricultural
intermediate.

Means for Solving the Problems

[0014] The present inventors have found, as a result of extensive
researches made to solve the above problems, that it is possible to
produce an optically active fluorinated oxetane of the general formula
[3] by reaction of a fluorinated α-keto ester of the general
formula [1] with an acyl alkenyl ether of the general formula [2] in the
presence of "a transition metal complex with an optically active ligand".

[0015] The fluorinated α-keto ester of the general formula [1] is
preferably one having a trifluoromethyl group as a perfluoroalkyl group
and a methyl group or an ethyl group as an alkyl group of its ester
moiety so that the fluorinated α-keto ester can be easily available
on a large scale. The acyl alkenyl ether of the general formula [2] is
preferably one having a hydrogen atom or an alkyl group as a substituent
of its acyl moiety and hydrogen atoms as all of three substituents of its
alkenyl moiety so that the acyl alkenyl ether can be easily available on
a large scale and at low cost. Further, the transition metal complex with
the optically active ligand is preferably a divalent cationic transition
metal complex with an optically active ligand, more preferably a divalent
cationic palladium complex with an optically active ligand. The desired
reaction can proceed favorably by the use of such a complex.

[0016] The optically active fluorinated oxetane of the general formula [3]
obtained by the production method of the present invention is a novel
compound that can be an important pharmaceutical or agricultural
intermediate. Among others, preferred examples of the optically active
fluorinated oxetane are those in which: the perfluoroalkyl group is a
trifluoromethyl group; the alkyl moiety of the ester moiety is a methyl
group or an ethyl group; the substituent of the acyl moiety is a hydrogen
atom or an alkyl group; and all of the other three substituents on the
oxetane ring are hydrogen atoms. These oxetane compounds can be produced
on a large scale and can be a particularly important pharmaceutical or
agricultural intermediate.

[0017] As mentioned above, the present inventors have found useful
techniques for production of the novel optically active fluorinated
oxetane compound. The present invention is made based on such findings.

[0018] Namely, the present invention provides a practical production
method of an optically active fluorinated oxetane, which can be an
important pharmaceutical or agricultural intermediate, as defined in the
following Inventive Aspects 1 to 5.

[0019] [Inventive Aspect 1]

[0020] A method for producing an optically active fluorinated oxetane of
the general formula [3], comprising: reacting a fluorinated α-keto
ester of the general formula [1] with an acyl alkenyl ether of the
general formula [2] in the presence of a transition metal complex with an
optically active ligand,

##STR00002##

where Rf represents a perfluoroalkyl group; and R1 represents an
alkyl group;

##STR00003##

where R2, R3, R4 and R5 each independently represent
a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic
ring group or a substituted aromatic ring group; and

##STR00004##

where Rf, R1, R2, R3, R4 and R5 are the same as
above: * represents an asymmetric carbon atom (when R4 and R5
are the same substituents, a carbon atom to which R4 and R5 are
bonded is not an asymmetric carbon atom); and the wavy lines indicate
that the configuration of acyloxy (R2CO2) group relative to Rf
and the configuration of R4 relative to Rf are each independently a
syn configuration, an anti configuration or a mixture thereof.

[0021] [Inventive Aspect 2]

[0022] A method for producing an optically active fluorinated oxetane of
the general formula [6], comprising: reacting a fluorinated α-keto
ester of the general formula [4] with an acyl alkenyl ether of the
general formula [5] in the presence of a divalent cationic transition
metal complex with an optically active ligand,

##STR00005##

where R6 represents a methyl group or an ethyl group;

##STR00006##

where R7 represents a hydrogen atom or an alkyl group; and

##STR00007##

where R6 and R7 are the same as above; * represents an
asymmetric carbon atom; and the wavy line indicates that the
configuration of acyloxy (R7CO2) group relative to CF3
group is a syn configuration, an anti configuration or a mixture thereof.

[0023] [Inventive Aspect 3]

[0024] The method for producing the optically active fluorinated oxetane
according to Inventive Aspect 2, wherein the divalent cationic transition
metal complex with the optically active ligand is a divalent cationic
palladium complex with an optically active ligand.

[0025] [Inventive Aspect 4]

[0026] An optically active fluorinated oxetane of the general formula [3]

##STR00008##

where Rf represents a perfluoroalkyl group; R1 represents an alkyl
group; R2, R3, R4 and R5 each independently represent
a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic
ring group or a substituted aromatic ring group; * represents an
asymmetric carbon atom (when R4 and R5 are the same
substituents, a carbon atom to which R4 and R5 are bonded is
not an asymmetric carbon atom); and the wavy lines indicate that the
configuration of acyloxy (R2CO2) group relative to Rf and the
configuration of R4 relative to Rf are each independently a syn
configuration, an anti configuration or a mixture thereof.

[0027] [Inventive Aspect 5]

[0028] An optically active fluorinated oxetane of the general formula [6]

##STR00009##

where R6 represents a methyl group or an ethyl group; R7
represents a hydrogen atom or an alkyl group; * represents an asymmetric
carbon atom; and the wavy line indicates that the configuration of
acyloxy (R7CO2) group relative to CF3 group is a syn
configuration, an anti configuration or a mixture thereof.

DETAILED DESCRIPTION

[0029] The production method of the present invention utilizes a catalytic
asymmetric synthesis process and does not require a stoichiometric amount
of chiral source so that it is possible to dramatically reduce the amount
of asymmetric catalyst used especially when the reaction is performed at
a high concentration of substrate (with the use of a small amount of
reaction solvent) or in the absence of a reaction solvent (under neat
conditions). Further, the target optically active fluorinated oxetane can
be obtained with high yield and with very high optical purity. The
product contains almost no difficult-to-separate impurity and shows high
chemical purity. The usability of the production method of the present
invention is thus clear.

[0030] In this way, the present invention enables practical production of
the optically active fluorinated oxetane that can be an important
pharmaceutical or agricultural intermediate.

[0031] The production method of the optically active fluorinated oxetane
according to the present invention will be described in detail below.

[0032] In the fluorinated α-keto ester of the general formula [1],
Rf represents a perfluoroalkyl group. Examples of the perfluoroalkyl
group as Rf are those of 1 to 12 carbon atoms. The perfluoroalkyl group,
when having 3 or more carbon atoms, can be in the form of a linear,
branched or cyclic structure. In the fluorinated α-keto ester of
the general formula [1], R1 represents an alkyl group. Examples of
the alkyl group as R1 are those of 1 to 12 carbon atoms. The alkyl
group, when having 3 or more carbon atoms, can be in the form of a
linear, branched or cyclic structure. Among others, it is preferable to
use a fluorinated α-keto ester having a trifluoromethyl group as Rf
and a methyl or ethyl group as R1, which can be easily produced and
industrially applicable, for production of the optically active
fluorinated oxetane.

[0033] It suffices to use the fluorinated α-keto ester of the
general formula [1] in an amount of 0.2 mol or more per 1 mol of the acyl
alkenyl ether of the general formula [2]. The amount of the fluorinated
α-keto ester of the general formula [1] used is preferably 0.3 to 7
mol, more preferably 0.4 to 5 mol, per 1 mol of the acyl alkenyl ether of
the general formula [2].

[0034] In the acyl alkenyl ether of the general formula [2], R2,
R3, R4 and R5 each independently represent a hydrogen
atom, an alkyl group, a substituted alkyl group, an aromatic ring group
or a substituted aromatic ring group. Examples of the alkyl group as
R2, R3, R4, R5 are those of 1 to 12 carbon atoms. The
alkyl group, when having 3 or more carbon atoms, can be in the form of a
linear, branched or cyclic structure. Examples of the aromatic ring group
are those of 1 to 18 carbon atoms, including an aromatic hydrocarbon
groups, such as phenyl, naphthyl or anthryl and an aromatic heterocyclic
group containing a heteroatom e.g. nitrogen, oxygen or sulfur, such as
pyrrolyl, furyl, thienyl, indolyl, benzofuryl or benzothienyl.

[0035] Examples of the substituted alkyl group and the substituted
aromatic ring group are those in which any of the carbon atoms of the
alkyl group and the aromatic ring group are replaced with any number of
and any combination of substituents. As such substituents, there can be
used: halogen atoms such as fluorine, chlorine, bromine and iodine; azide
group; nitro group; lower alkyl groups such as methyl, ethyl and propyl;
lower haloalkyl groups such as fluoromethyl, chloromethyl and
bromomethyl; lower alkoxy groups such as methoxy, ethoxy and propoxy;
lower haloalkoxy groups such as fluoromethoxy, chloromethoxy and
bromomethoxy; lower alkylamino groups such as dimethylamino, diethylamino
and dipropylamino; lower alkylthio groups such as methylthio, ethylthio
and propylthio; cyano group; lower alkoxycarbonyl groups such as
methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; aminocarbonyl group;
lower alkylaminocarbonyl groups such as dimethylaminocarbonyl,
diethylaminocarbonyl and dipropylaminocarbonyl; unsaturated groups such
as lower alkenyl groups and lower alkynyl groups; aromatic ring groups
such as phenyl, naphthyl, pyrrolyl, furyl and thienyl; aromatic ring oxy
groups such as phenoxy, naphthoxy, pyrrolyloxy, furyloxy and thienyloxy;
aliphatic heterocyclic groups such as piperidyl, piperidino and
morpholinyl; hydroxyl group; protected hydroxyl groups; amino groups
(including amino acids or peptide residues); protected amino groups;
thiol group; protected thiol groups; aldehyde group; protected aldehyde
groups; carboxyl group; and protected carboxyl groups.

[0036] In the present specification, the following terms are herein
defined by the following meanings. The term "lower" means that the group
to which the term is attached has 1 to 6 carbon atoms in the form of a
linear structure, a branched structure or a cyclic structure (in the case
of 3 or more carbon atoms). It means that, when the "unsaturated group"
is a double bond (alkenyl group), the double bond can be in either or
both of E and Z geometries. The "protected hydroxyl, amino, thiol,
aldehyde and carboxyl groups" may refer to those having protecting groups
as described in "Protective Groups in Organic Synthesis", Third Edition,
1999, John Wiley & Sons, Inc. (In this case, two or more functional
groups may be protected with one protecting group.)

[0037] Further, the "unsaturated group", "aromatic ring group", "aromatic
ring oxy group" and "aliphatic heterocyclic group" may be substituted
with halogen atoms, azide group, nitro group, lower alkyl groups, lower
haloalkyl groups, lower alkoxy groups, lower haloalkoxy groups, lower
alkylamino groups, lower alkylthio groups, cyano group, lower
alkoxycarbonyl groups, aminocarbonyl group, lower alkylaminocarbonyl
groups, hydroxyl group, protected hydroxyl groups, amino group, protected
amino groups, thiol group, protected thiol groups, aldehyde group,
protected aldehyde groups, carboxyl group or protected carboxyl groups.
Although some of these substituent groups may be involved in a side
reaction, the desired reaction can be promoted favorably by the adoption
of suitable reaction conditions. Among others, it is preferable to use an
acyl alkenyl ether having a hydrogen atom or alkyl group as R2 and
hydrogen atoms as all of R3, R4 and R5, which can be
produced at low cost and industrially applicable, for production of the
optically active fluorinated oxetane. In some case, it may be possible to
obtain a favorable result by subjecting the acyl alkenyl ether to
distillation purification before the reaction.

[0038] Although an alkyl alkenyl ether and a silyl alkenyl ether are
similar to the acyl alkenyl ether, each of the alkyl alkenyl ether and
the silyl alkenyl ether is unstable toward Lewis acids and readily
polymerized. It is thus necessary to use an asymmetric catalyst of weak
Lewis acidity (impossible to use an asymmetric catalyst of strong Lewis
acidity) in combination with the alkyl alkenyl ether or silyl alkenyl
ether so that the amount of the asymmetric catalyst used cannot be
reduced dramatically. In the case of the alkyl alkenyl ether, a desired
oxetane structure cannot be formed during the reaction. In the case of
the silyl alkenyl ether, it is necessary for the formation of an oxetane
structure to use a silyl alkenyl ether having a sterically bulky silyl
group, such as triisopropyl silyl alkenyl ether, that is expensive as the
raw material substrate.

[0039] Examples of the transition metal complex with the optically active
ligand are divalent cationic transition metal catalysts with optically
active ligands as represented by the general formula [7]

Other example of the transition metal complex with the optically active
ligand are BINOL-Ti complexes as represented by the general formula [8]

##STR00018##

where R represents a hydrogen atom, a chlorine atom, a bromine atom, an
iodine atom or a trifluoromethyl group; and Me represents a methyl group.

[0047] Among others, it is preferable to use a divalent cationic
transition metal complex with an optically active ligand, more preferably
a divalent cationic palladium complex with an optically active ligand.
(Although typical examples of the optically active ligand are mentioned
above, there can suitably be used as the optically active ligand any
appropriate one of those described in "Catalytic Asymmetric Synthesis",
Second Edition, 2000, Wiley-VCH, Inc. As Z, SbF6, BF4, OTf and
B(3,5-(CF3)2C6H3)4 are preferred. Particularly
preferred are SbF6, OTf and
B(3,5-(CF3)2C6H3)4.)

[0048] These complexes can be prepared by any known process (see e.g.
Tetrahedron Letters (U.K.), 2004, Vol. 45, P. 183-185; Tetrahedron:
Asymmetry (U.K.), 2004, Vol. 15, P. 3885-3889; Angew. Chem. Int. Ed.
(Germany), 2005, Vol. 44, P. 7257-7260; J. Org. Chem. (U.S.), 2006, Vol.
71, P. 9751-9764; J. Am. Chem. Soc. (U.S.), 1999, Vol. 121, P. 686-699;
Nature (U.K.), 1997, Vol. 385, P. 613-615). The complex can be provided
in isolate form or can be prepared in advance in the reaction system and
used without isolation. Further, the complex may be in the form of having
a coordinate bond (solvation) with water or organic solvent such as
acetonitrile.

[0049] There may be used, in the same manner as the divalent cationic
transition metal complex with the optically active ligand as represented
by the general formula [7], a cationic binuclear transition metal complex
with an optically active ligand as represented by the general formula [9]

##STR00019##

where X--*--X, Y and Z are the same as in the general formula [7].

[0050] The configuration ((R), (S), (R,R), (S,S) etc.) of the optically
active ligand can be selected as appropriate depending on the
configuration of the target optically active fluorinated oxetane. The
optical purity of the optically active ligand can also be set as
appropriate depending on the optical purity of the target optically
active fluorinated oxetane. In general, it suffices that the optical
purity (enantiomer excess) of the optically active ligand is 95% ee or
higher. The optical purity (enantiomer excess) of the optically active
ligand is preferably 97% ee, more preferably 99% ee. Among the above
optically active ligands, the BINAP derivative is suitably used for the
reason that the BINAP derivative can be most cheaply available in the
form of both enantiomers and, when derived into an asymmetric catalyst,
attain very high activity. As the BINAP derivative, BINAP and Tol-BINAP
are preferred. Particularly preferred is BINAP.

[0051] It suffices to use the transition metal complex with the optically
active ligand in an amount of 0.4 mol or less per 1 mol of the acyl
alkenyl ether of the general formula [2]. The amount of the transition
metal complex with the optically active ligand used is preferably 0.3 to
0.00001 mol, more preferably 0.2 to 0.0001 mol, per 1 mol of the acyl
alkenyl ether of the general formula [2].

[0052] Examples of the reaction solvent are: aliphatic hydrocarbon
solvents such as n-pentane, n-hexane, cyclohexane and n-heptane; aromatic
hydrocarbon solvents such as benzene, toluene, xylene and mesitylene;
halogenated hydrocarbon solvents such as methylene chloride, chloroform
and 1,2-dichloroethane; and ether solvents such as diethyl ether,
tert-butyl methyl ether and 1,4-dioxane. Among others, aromatic
hydrocarbon solvents, halogenated hydrocarbon solvents and ether solvents
are preferred. Particularly preferred are aromatic hydrocarbon solvents
and halogenated hydrocarbon solvents. These reaction solvents can be used
solely or in combination thereof. In the production method of the present
invention, the reaction can be performed in the absence of the reaction
solvent (i.e. under neat conditions). This is one preferred embodiment of
the present invention as it is possible to dramatically reduce the amount
of use of the transition metal complex with the optically active ligand.

[0053] In the case of using the reaction solvent, there is no particular
limitation on the amount of the reaction solvent used. It suffices to use
the reaction solvent in an amount of 0.01 L or more per 1 mol of the acyl
alkenyl ether of the general formula [2]. The amount of the reaction
solvent used is preferably 0.05 to 50 L, more preferably 0.1 to 30 L, per
1 mol of the acyl alkenyl ether of the general formula [2]. In the
production method of the present invention, the reaction can be performed
at a high concentration of substrate (i.e. with the use of a small amount
of reaction solvent). This is also one preferred embodiment of the
present invention as it is possible to dramatically reduce the amount of
use of the transition metal complex with the optically active ligand. For
such a substrate concentration, it suffices to use the reaction solvent
in an amount of less than 1 L per 1 mol of the acyl alkenyl ether of the
general formula [2]. The amount of the reaction solvent used is
preferably 0.5 L or less, more preferably 0.3 L or less, per 1 mol of the
acyl alkenyl ether of the general formula [2].

[0054] It suffices that the reaction temperature is in a range of -80 to
+150° C. The reaction temperature is preferably -70 to
+125° C., more preferably -60 to +100° C.

[0055] Further, it suffices that the reaction time is in a range of 72
hours or less. As the reaction time depends on the raw material
substrate, the asymmetric catalyst and the reaction conditions, it is
preferable to determine the time at which the raw material substrate has
almost disappeared as the end of the reaction while monitoring the
progress of the reaction by any analytical means such as gas
chromatography, thin layer chromatography, liquid chromatography or
nuclear magnetic resonance (NMR).

[0056] The target optically active fluorinated oxetane of the general
formula [3] is obtained by post treatment of the reaction terminated
liquid. The post treatment can be performed by ordinary operation in
organic synthesis. The obtained crude product can be purified to a high
purity, as required, by purification operation such as activated carbon
treatment, distillation, recrystallization or column chromatography. The
asymmetric catalyst used in the present invention is one kind of Lewis
acid. Even in the case where the target product is unstable toward acids,
it is possible to effectively prevent decomposition of the target product
and occurrences of side reactions by performing the reaction under
low-temperature conditions and directly adding an organic base (catalyst
poison) such as triethylamine to the reaction terminated liquid. The
high-purity product can be obtained by relatively easy operation of
directly passing the mixed solution of the reaction terminated liquid and
the organic base (as the treated reaction solution) through a short
column, concentrating the filtrate and purifying the concentration
residue by column chromatography.

[0057] When R4 or R5 is a hydrogen atom in the acyl alkenyl
ether of the general formula [2], the optically active fluorinated
oxetane product of the general formula [3] may undergo ring-opening
reaction and thereby be obtained in a ring-open form of the general
formula [10]

##STR00020##

where Rf represents a perfluoroalkyl group; R1 represents an alkyl
group; R2, R3, R4 and R5 each independently represent
a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic
ring group or a substituted aromatic ring group; * represents an
asymmetric carbon atom; and the wavy lines indicate that the double bond
is in either or both of E and Z geometries.

[0058] The optically active fluorinated oxetane of the general formula [3]
as claimed in the present invention is thus defined as including the
optically active fluorinated oxetane ring-open product of the general
formula [10].

EXAMPLES

[0059] The present invention will be described in more detail below by way
of the following examples. It should be noted that these examples are
illustrative and are not intended to limit the present invention thereto.

[0060] Herein, Examples 2 to 8 were performed in the same manner as in
Example 1. The results of Examples 1 to 9 are summarized in TABLE 1. The
substrate concentration were 2 M, 1 M and 0.5 M when the amount of the
reaction solvent used was 0.5 L, 1 L and 2 L with reference to 1 mol of
the raw material substrate, respectively.

Example 1

[0061] To 1.0 mL of toluene, 8.0 mg (0.01 mmol) of (R)-BINAP-PdCl2
represented by the following formula:

##STR00021##

and 7.6 mg (0.022 mmol) of AgSbF6 were added in a nitrogen
atmosphere. The resulting solution was stirred for 30 minutes at room
temperature (to thereby form a divalent cationic transition metal complex
with an optically active ligand as represented by the general formula [7]
(X--*--X: (R)-BINAP, Y: Pd, Z: SbF6) in the reaction system).

[0062] To the solution, 34.0 mg (0.2 mmol) of fluorinated α-keto
ester of the following formula:

##STR00022##

and 8.6 mg (0.1 mmol) of acyl alkenyl ether of the following formula:

##STR00023##

were added at -20° C. The solution was then stirred for 15 hours
as the same temperature (as a reaction terminated liquid) and treated
with the addition of 218 mg (2.2 mmol) of triethylamine.

[0063] The treated reaction solution was directly passed through a short
column (silica gel/ethyl acetate:n-hexane=1:1). The filtrate was
concentrated under a reduced pressure. The concentration residue was
subjected to 1H-NMR quantitative analysis. It was confirmed that
there was contained in the residue 22.8 mg of (+)-isomer of optically
active fluorinated oxetane of the following formula:

##STR00024##

[0064] The yield was 89%. The diastereoisomer ratio was determined by
1H-NMR to be 23/77. Further, the enantiomer excess were determined
by chiral gas chromatography (CP-Chirasil-Dex CB) to be 91% ee and 98%
ee, respectively. The 1H-, 13C- and 19F-NMR data are
indicated below.

[0068] To 1.70 g (10 mmol) of fluorinated α-keto ester of the
following formula:

##STR00025##

4.0 mg (0.005 mmol) of (R)-BINAP-PdCl2 represented by the following
formula:

##STR00026##

and 3.8 mg (0.011 mmol) of AgSbF6 were added in a nitrogen
atmosphere. The resulting solution was stirred for 30 minutes at room
temperature (to thereby form a divalent cationic transition metal complex
with an optically active ligand as represented by the general formula [7]
(X--*--X: (R)-BINAP, Y: Pd, Z: SbF6) or a complex of the divalent
cationic transition metal complex with the optically active ligand and
the fluorinated α-keto ester as represented by the following
formula:

##STR00027##

in the reaction system).

[0069] To the solution, 430 mg (5 mmol) of acyl alkenyl ether of the
following formula:

##STR00028##

was added at -20° C. The solution was then stirred for 48 hours as
the same temperature (as a reaction terminated liquid) and treated with
the addition of 218 mg (2.2 mmol) of triethylamine.

[0070] The treated reaction solution was directly passed through a short
column (silica gel/ethyl acetate:n-hexane=1:1). The filtrate was
concentrated under a reduced pressure. The concentration residue was
purified by column chromatography (silica gel/ethyl
acetate:n-hexane=1:4). With this, there was obtained 1.10 g of (+)-isomer
of optically active fluorinated oxetane of the following formula:

##STR00029##

[0071] The yield was 86%. The diastereoisomer ratio was determined by
1H-NMR to be 8/92. The enantiomer excess were determined by chiral
gas chromatography (CP-Chirasil-Dex CB) to be 20% ee and 96% ee,
respectively. The specific rotation was [α]D24+48.86
(c=1.13 in CHCl3). The 1H-, 13C- and 19F-NMR data
were the same as those of Example 1.

[0072] To 5.00 g (29.4 mmol) of fluorinated α-keto ester of the
following formula:

##STR00032##

120 mg (0.150 mmol) of (S)-BINAP-PdCl2 represented by the following
formula:

##STR00033##

and 113 mg (0.329 mmol) of AgSbF6 were added in a nitrogen
atmosphere. The resulting solution was stirred for 30 minutes at room
temperature (to thereby form a divalent cationic transition metal
catalyst with an optically active ligand as represented by the general
formula [7] (X--*--X: (S)-BINAP, Y: Pd, Z: SbF6) or a complex of the
divalent cationic transition metal complex with the optically active
ligand and the fluorinated α-keto ester as represented by the
following formula:

##STR00034##

in the reaction system).

[0073] To the solution, 46.0 g (270 mmol) of fluorinated α-keto
ester of the following formula:

##STR00035##

and 12.9 g (150 mmol) of acyl alkenyl ether of the following formula:

##STR00036##

were added at -20° C. The solution was then stirred for 48 hours
as the same temperature (as a reaction terminated liquid) and treated
with the addition of 6.68 g (66.0 mmol) of triethylamine.

[0074] The treated reaction solution was directly passed through a short
column (silica gel/ethyl acetate:n-hexane=1:1). The filtrate was
concentrated under a reduced pressure. The concentration residue was
subjected to 19F-NMR quantitative analysis. It was confirmed that
there was contained in the residue 20.3 g of (-)-isomer of optically
active fluorinated oxetane of the following formula:

##STR00037##

[0075] The yield was 53%. The crude product was purified by fractional
distillation (boiling point: 106° C./vacuum degree: 0.7 kPa),
thereby yielding 17.3 g of a main fraction. The recovery rate was 85%
(the total yield was 45%). The diastereoisomer ratio of the main fraction
was determined by gas chromatography to be 4/96. Further, the enantiomer
excess of the main diastereomer was determined by chiral gas
chromatography (CP-Chirasil-Dex CB) to be 98% ee. The 1H- and
19F-NMR data were the same as those of Example 1.

Example 11

[0076] To 5.00 g (29.4 mmol) of fluorinated α-keto ester of the
following formula:

##STR00038##

120 mg (0.150 mmol) of (S)-BINAP-PdCl2 represented by the following
formula:

##STR00039##

and 113 mg (0.329 mmol) of AgSbF6 were added in a nitrogen
atmosphere. The resulting solution was stirred for 30 minutes at room
temperature (to thereby form a divalent cationic transition metal complex
with an optically active ligand as represented by the general formula [7]
(X--*--X: (S)-BINAP, Y: Pd, Z: SbF6) or a complex of the divalent
cationic transition metal complex with the optically active ligand and
the fluorinated α-keto ester as represented by the following
formula:

##STR00040##

in the reaction system).

[0077] To the solution, 46.0 g (270 mmol) of fluorinated α-keto
ester of the following formula:

##STR00041##

and 15.0 g (150 mmol) of acyl alkenyl ether of the following formula:

##STR00042##

were added at -20° C. The solution was then stirred for 48 hours
as the same temperature (as a reaction terminated liquid) and treated
with the addition of 6.68 g (66.0 mmol) of triethylamine.

[0078] The treated reaction solution was directly passed through a short
column (silica gel/ethyl acetate:n-hexane=1:1). The filtrate was
concentrated under a reduced pressure. The concentration residue was
subjected to 19F-NMR quantitative analysis. It was confirmed that
there was contained in the residue 22.0 g of (-)-isomer of optically
active fluorinated oxetane of the following formula:

##STR00043##

[0079] The yield was 54%. The crude product was purified by fractional
distillation, thereby yielding 18.6 g of a main fraction. The recovery
rate was 85% (the total yield was 46%). The diastereoisomer ratio of the
main fraction was determined by gas chromatography to be 4/96. Further,
the enantiomer excess of the main diastereomer was determined by chiral
gas chromatography (CP-Chirasil-Dex CB) to be 97% ee. The 1H- and
19F-NMR data are indicated below.